Is valproate's brain target in treating bipolar disorder an arachidonic acid selective acyl‐coA synthetase?

In vivo chronic valproate (VPA) reduce arachidonic acid (AA, 20:4 n‐6) turnover but not docosahexaenoic acid (DHA, 22:6 n‐3) in brain phospholipids of unanesthetized rats. It has been ascribed to its inhibition of acyl‐CoA synthetase (Acsl)‐mediated activation of AA to AA‐CoA and DHA to DHA‐CoA respectively. Our aim was to identify a rat Acsl isoenzyme that could be inhibited by VPA in vitro. Rat Acsl3‐, Acsl6v1‐ and Acsl6v2‐, and Acsl4‐flag proteins were expressed in E. coli, and the ability of VPA to inhibit their activation of long‐chain fatty acids to acyl‐CoA was estimated using Michaelis‐Menten kinetics. VPA uncompetitively inhibited Acsl4‐mediated conversion of AA and of docosahexaenoic but not of palmitic acid to acyl‐CoA, but did not affect AA to AA‐CoA conversion by Acsl3, Acsl6v1 or Acsl6v2. Acsl4‐mediated conversion of AA to AA‐CoA showed substrate inhibition, and had a 10‐times higher catalytic efficiency than did conversion of DHA to DHA‐CoA. Butyrate, octanoate, or lithium did not inhibit AA activation by Acsl4. VPA's ability to inhibit Acsl4 activation of AA and of DHA to their respective acyl‐CoAs, related to the higher catalytic efficiency of AA than DHA conversion, may account for VPA's selective reduction of AA turnover in rat brain phospholipids, and contribute to VPA's efficacy against bipolar disorder. This work was entirely supported by the intramural program of NIA.